Matrix stiffness modulates hepatic stellate cell activation into tumor-promoting myofibroblasts via E2F3-dependent signaling and regulates malignant progression

• Published in: Cell death & disease 2021-12, Vol.12 (12), p.1134-1134, Article 1134
• Main Authors: Liu, Zhikui, Mo, Huanye, Liu, Runkun, Niu, Yongshen, Chen, Tianxiang, Xu, Qiuran, Tu, Kangsheng, Yang, Nan
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 38/89; 631/67/1504/1610; 631/80/304; 82/51; 82/80; 96/1; 96/35; Actin; AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carbon tetrachloride; Carcinoma, Hepatocellular - pathology; CD36 antigen; Cell activation; Cell Biology; Cell Culture; Cell differentiation; Cell Proliferation - genetics; E2F3 Transcription Factor - metabolism; Extracellular matrix; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibroblast growth factor receptor 1; Fibrosis; Hepatic Stellate Cells - metabolism; Hepatocellular carcinoma; Immunofluorescence; Immunology; Life Sciences; Liver; Liver Cirrhosis - metabolism; Liver Neoplasms - pathology; Mechanical stimuli; Metastases; Metastasis; Mice; Microenvironments; Mitogen-Activated Protein Kinase Kinases - metabolism; Myofibroblasts - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering - metabolism; Signal transduction; Smooth muscle; Stellate cells; Stromal cells; Transcription; Tumor cells; Tumor Microenvironment
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04418-9

The hepatic stellate cells (HSCs) activation by myofibroblastic differentiation is critical for liver fibrosis. Crosstalk between stromal cells and tumor cells in the microenvironment alters the properties and facilitates the growth and metastasis of tumor cells. How mechanical stimuli originally stiffness of extracellular matrix (ECM) contribute to tumor development remains poorly understood. Here, we demonstrated that stiffness contributes to mechanosignal transduction in HSCs, which promotes hepatocellular carcinoma (HCC) cells growth and metastasis through secretion of FGF2. On stiffness matrix, HSCs activation was confirmed by immunofluorescence (IF) and Western blot (WB) for α-smooth muscle actin (SMA). Increasing matrix stiffness promoted HSCs activation by CD36-AKT-E2F3 mechanosignaling through shRNA-mediated E2F3 knockdown, AKT inhibitors, and CD36 shRNA. Moreover, ChIP-qPCR. Confirmed that E2F3 combined the promoter of FGF2, and stiffness promoted FGF2 expression. On a stiff matrix, HCC cells cultured with conditioned media (CM) from HSCs increased HCC cells growth and metastasis by binding FGFR1 to activate PI3K/AKT and MEK/ERK signaling pathways. Moreover, conditional E2F3 knockout mice were subjected to CCl4 treatment to assess the role of E2F3 in HSC activation. Additionally, the DEN-induced HCC model was also used to evaluate the role of E2F3 in liver fibrosis and HCC growth. In conclusion, we demonstrated that stiffness-induced HSC activation by E2F3 dependent. Stiffness activated CD36-AKT-E2F3 signaling and targeted FGF2 transcription, subsequently, activated HCC growth and metastasis by FGFR1-mediated PI3K/AKT and MEK/ERK signaling.